Process for the preparation of 1-(3,4-dimethoxyphenyl)ethanol

ABSTRACT

The subject of our invention is the process for the preparation of the 1-(3,4-dimethoxyphenyl)ethanol of formula (I), by the reduction of 3,4-dimethoxyacetophenone of formula (II), characterized in that the carbonyl group of the 3,4-dimethoxyacetophenone of formula (II) is reduced by 1 mol of hydrogen under the conditions of catalytic hydrogenation.

This application is the national phase under 35 U.S.C. §371 of PCTInternational Application No. PCT/HU98/00072 which has an Internationalfiling date of Jul. 28, 1998, which designated the United States ofAmerica.

The subject of the present invention is the heterogenous catalytichydrogenation process, suitable for scaling up, for the synthesis of1-(3,4-dimethoxyphenyl)ethanol (by other name α-methylveratryl alcohol)of formula I. by the reduction of 3,4-dimethoxyacetophenone of formulaII.

The title compound is the starting material to a number of importantcompounds and there is a growing demand for it. Among others, it canfavourably be used for the preparation of the insecticide synergistsdescribed in WO 97/19040 and Hungarian patent applications No 3318/95and 0893/97. Therefore, elaboration of an economical technology wasrequired. It was necessary that the crude product obtained in theprocess be of high purity and not require purification operations, likefor instance distillation. The 1-phenylethanols substituted with methoxygroups are namely surprisingly sensitive compounds and they can bepurified only with substantial losses. On the effect of heat during thedistillation, and/or on the effect of traces of acids or bases the abovecompounds readily transform into the bis-phenylethyl ethers of formulaIII (Chem. Pharm. Bull. 31, 3024 (1983); J. Chem. Soc. 3158 (1957); J.Am. Chem. Soc. 70, 1895 (1948)), or via dehydration they can form thestyrene derivative of formula IV. (J. Am. Chem. Soc. 106, 1361 (1984)).

In the literature there are two basic methods for the synthesis of1-(3,4-dimethoxyphenyl)ethanol. According to the first method thecompound is prepared by the reaction of 3,4-dimethoxybenzaldehyde andmethylmagnesium iodide (Chem. Pharm. Bull. 31, 3024 (1983)); accordingto the second by the reduction of 3′,4′-dimethoxyacetophenone (by othername acetoveratrone). The latter reduction can be performed by usingsodium borohydride (Bull. Soc. Chim. France 1973 2667; J. Chem. Soc.Perkin 2 1994, 961; J. Am. Chem Soc. 86, 1186 (1964)), tributyltinhydride (J. Org. Chem. 59 7138 (1994)), sodium in ethanol (Arch. Pharm(Weinheim Ger.) 248, 139 (1910)), or aluminium isopropoxide (Ann. 1995,677) in isopropanol. None of the above methods is suitable forlarge-scale technology, considering the costly reagents, the specificreaction conditions (eg. anhydrous solvents), the resulting wastematerials, as well as the complicated work-up and purificationprocedures.

There is no reference in the literature for the heterogeneous catalytichydrogenation of the acetoveratrone of formula II. This is surprising,since this route seems to be the most economical for the preparation ofthe compound of formula I, in an industrial scale.

Hydrogenation of the carbonyl group requires active catalyst. For thereduction of acetophenones catalysts as platinum metals (platinum,palladium, rhodium, ruthenium, iridium) (Ann. 1924, 276; J. Org. Chem.24, 1885 (1959); Bull. Chem. Soc. Jpn. 34, 32 (1961)), nickel (J. Am.Chem Soc. 52, 4349 (1930); J. Org. Chem. 45, 1937, 1946 (1980)),Raney-nickel (J. Am. Chem. Soc. 70, 695 (1948); J. Chem. Soc. 3158(1957); Ann. 714, 91 (1968); Bull. Soc. Chim. France 1972, 4324), orcopper chromite (J. Am. Chem. Soc. 53, 1090 (1931)) may be used. Theselectivity of these metals is, however, different. Rhodium catalyst isinclined to also saturate the ring, platinum, depending on the solventand the pH, may cause hydrogenolysis, i.e the ethylbenzene by-product offormula V, will appear. For the catalytic hydrogenation of acetophenonesthe literature suggests the use of 10% palladium-on charcoal catalyst(Paul Rylander, Catalytic Hydrogenation in Organic Synthesis; p103,Academic Press, 1979).

Our first experiments verified that the known methods cannot directly beused. Hydrogenation of the acetoveratrone of formula II, following theprocedure suggested by the literature, using 10% palladium-on charcoalcatalyst, under normal conditions (25° C., 1 atm), in methanol assolvent, did not lead to homogeneous product.. Beside the expected1-(3,4-dimethoxyphenyl)ethanol a high amount of ethylveratrole was alsoformed. The hydrogenation of the keto group and the hydrolysis of theC—O bond of the product proceeded simultaneously, at comparable rate,and in addition a considerable amount of 1-(3,4-dimethoxyphenyl)ethylmethyl ether by-product was also isolated. The electron-donating alkoxygroups activate the benzylic carbon atom to nucleofilic substitution,thus the latter in the given environment, for instance on the surface ofthe catalyst may react with a nucleophilic partner, in our case with thesolvent, i.e. alcohol, but it may even react with the product of thereduction, i.e. with the α-methylveratryl alcohol. To all this is addedthe sensitivity of the desired α-methylveratryl alcohol of formula I,which makes the accomplishment of the process even more difficult, andwhich also explains why hydrogenation was not used for the preparationof that compound.

The growing demand for the compound in question, as well as theinexpensive implementation of catalytic hydrogenations, inspired us,despite the above difficulties, to work out a hydrogenation processwhich is exempt from the above disadvantages, ie. which results thedesired compound of formula I in higher yield, higher purity and moreeconomically than the previous methods.

Although rarely, nickel and Raney-nickel are also used for thehydrogenation of phenones, the reactions being carried out mainly inethanolic or methanolic medium. According to the relevent literature asuccessful reaction requires rather drastic conditions (Paul Rylander,Catalytic Hydrogenation in Organic Synthesis, p83, Academic Press,1979). As a concequence, one can expect in these reactions as well, theappearance of the appropriate 1-phenylethyl ethyl or methyl ether. Theformation of this by-product can theoretically be exluded if aqueousmedium or neutral catalyst is applied. Even though, no example can befind in the literature for hydrogenation of the given group of compoundsin aqueous medium. The reason for that may be that the starting materialand the product as well are expected to be rather insoluble in water,their solvation does not proceed, while the surface of the catalyst isdeactivated, due to the polar solvate layer. (Paul Rylander, CatalyticHydrogenation in Organic Synthesis, p83, Academic Press, 1979), all ofthese will cause the slowing-down of the reduction, and in the light ofthe above, the formation of by-products. To investigate this point, wecalculated the partition ratio of acetoveratrone. To our surprise, arather low value (calculated 1 gP≅1.22, K(octanol, water)≅16) wasobtained. This means that the material has a weak, hydrophilic characterand a suitable polarity. By increasing the temperature this value mayfurther be ameliorated, which means that there was a chance that thereaction can proceed and the by-product formation can be suppressed.Carrying out the hydrogenation at a temperature higher than the meltingpoint of the starting material (50° C.), suitable dispersity andsolvation equlibrium may be ensured by vigourous stirring of the melt inthe aqueous medium. Our expectations have been proven by ourexperiments. We investigated the hydrogenation of acetoveratrone at20-80° C., by using neutral Raney-nickel catalyst. After 5-48 hours fulltransformation and the formation of homogeneous product was observed. Ifthe reaction was performed at 50-80° C., under 6-10 bar hydrogenpressure, full conversion was achieved in much shorter time, dependingon the intensity of the stirring (700-1250 l/min) the reactionaccomplished in 3-7 hours. The product was obtained from the reactionmixture following evaporation under reduced pressure. Yields were ineach case over 98%. As shown by analytical investigation (GC, HPLC, VRK)starting from a raw material of over 98% purity the assay for theproduct was higher than 97%. Total amuont of the unreacted startingmaterial and the ethylveratrole by-product was as little as about 0.5%.The high purity of the product is well shown by the phenomenon, that onstanding it crystallized, although previously this compound was onlyknown as a viscous oil and no data for its melting point have beendisclosed.

The subject of our invention, in accordance with the above, is a processfor the preparation of 1-(3,4-dimethoxyphenyl)ethanol of formula I., bythe reduction of 3,4-dimethoxyacetophenone of formula II, characterizedby, that the carbonyl group of the 3,4-dimethoxyacetophenone of formulaII is reduced with 1 mol of hydrogen under catalytic hydrogenationconditions. The reduction is preferably carried out by use ofRaney-nickel catalyst. in a protic solvent, preferably in aqueousmedium, at 25-100° C., preferably at a temperature between 50-100° C.,under a pressure of 1-20 bar, preferably under a pressure between 5-10bar.

As for Raney-nickel catalyst preferably neutral-weakly basic pH 7-9promoted Raney-nickel is applied, in an amount of 0.05-0.5 part of mass.

The present process has a number of advantages compared to thepreviously known processes:

the yield is practically quantitative,

the product can be isolated by filtration followed by a simpleevaporation, it is of high purity, it does not require furtherpurification,

the product is in crystalline form, thus it is more stable, more easy tohandle, and it can be stored better,

the catalyst which has been filtered off, can be re-used in the nextreduction,

the use of water as solvent is very advantageous, considering bothsafety and economy,

the technology has a good capacity factor, the reactor volume is wellutilized, while the reaction time is only a few hours,

waste materials, by-products are not formed.

Further details of the invention are demonstrated by the followingexamples, without limiting the claims to the examples.

EXAMPLE 1

Into a 10-L hydrogenation vessel, equipped with an internal coil forheating and cooling, stirrer, manometer and thermometer, 3.5 kg (19.4mol) of 3,4-dimethoxyacetophenone are placed and to it 0.26 kg (0.074mass part) slurry of finely-powdered Raney-nickel (pH=8-9) promotedcatalyst are washed with 1 kg of water. The reactor is filled with 3.5kg of water, flushed with nitrogen, then with hydrogen, and underintensive stirring (revolution per minute is approx. 1420 min⁻¹) themixture is reacted at 70-85° C. with hydrogen under 8-10 bar. After 7hours the hydrogen consumption is ceased. Closing the hydrogen inlet,the reaction is post-hydrogenated for half an hour, then it is cooled.The catalyst is removed by filtration. The filtrate is concentrated invacuo (20 torr) by a rotary evaporator, in a 40-50° C. water-bath.

The product is a yellow viscous oil, weight 3.48 kg (19.1 mol, 98.5%).Refractive index (Na_(D), 25° C.) is 1.5385; assay by HPLC is 97.3%;water content by Karl-Fisher method is 1,2%. TLC (Kieselgel 60 F₂₅₄benzene-EtAc 7:3 v/v) shows one spot (R_(f)=0.28, visualized by UV lightand PMA).

An aliquot part is crystallized from 1.5-fold volume of diethylether—light petroleum (2:1, v/v) mixture. Melting point of the thusobtained white crystals is 34-35° C.

Confirmation of Structure

IR(KBr,cm⁻¹) ν: 3312, 3056, 3006, 2966, 2926, 2880, 2844, 1608, 1594,1522, 1467, 1261, 1237, 1162, 1140, 1091, 1075, 1028, 861, 814.

¹H-NMR (200 MHz, CDCl₃) δ: 1.47 (3H, d, J=6.4 Hz, CH₃), 2.08 (1H, s,OH), 3.86 and 3.88 (total 6H, each s, CH₃O), 4.83 (1H, q, J=6.4 Hz,CHOH), 6.79-6.93 (3H, m, aromatic).

¹³C-NMR (50 MHz, CDCl₃) δ: 25.05 (CH₃), 55.79 and 55.89 (CH₃O), 70.10(ArCH), 108.65 (C-2), 110.98 (C-5), 117.48 (C-6), 138.57 (C-1), 148.28and 149.0 (C-3, C-4).

Literature Data

CAS No: 5653-65-6

CA name: 1-(3,4-dimethoxyphenyl)-ethanol

B.p. 145-150 (4 torr), refractive index (Zhur. Obshchei Khim. 27, 2142(1957), CA 52; 8089 g) (Na_(D) 20° C.) 1.5440.

¹H-NMR (200 MHz, CDCl₃) δ: 1.48 (d, J=6.5 Hz), 3.86 and 0.89 (s), 4.84(q), 6.8-6.94 (m).

¹³C-NMR (Ann. 1977. 588) (50 MHz, CDCl₃) δ: 25.0, 55.8, 55.9, 70.1,108.7, 111.1, 117.5, 138.6, 148.4, 149.1.

EXAMPLE 2

Into a hydrogenation vessel, equipped with an internal coil for heatingand cooling, manometer and thermometer 50 g (0.278 mol) of3,4-dimethoxy-acetophenone are placed and to it 7.5 g (0.15 mass part)slurry of finely-powdered Raney-nickel (pH=8-9) promoted catalyst arewashed with 50 ml of water. The reactor is flushed with nitrogen, thenwith hydrogen, and is reacted at 70-85° C. with hydrogen under 8-10 bar,while agitating with a shaker. After 3.5 hours the hydrogen consumptionis ceased. Closing the hydrogen inlet, the reaction is post-hydrogenatedfor half an hour; then it is cooled. The catalyst is removed byfiltration. From the filtrate water is evaporated in vacuo (20 torr) bya rotary evaporator, in a 40-50° C. water-bath. The produc is a yellowviscoseous oil, mass: 49.6 g (0.273 mol, 98%). The quality of theproduct is similar to that of the product obtained in Example 1.

What is claimed is:
 1. A process for the preparation of1-(3,4-dimethoxyphenyl)ethanol of formula I

by the reduction of 3,4-dimethoxyacetophenone of formula II, wherein thecarbonyl group of 3,4-dimethoxyacetophenone of formula II

is reduced by 1 mol of hydrogen under catalytical hydrogenationconditions wherein Raney Nickel is used as catalyst under aqueousconditions.
 2. Process according to claim 1, characterized by, that thereduction is carried out by using a Raney-nickel catalyst.
 3. Theprocess according to claim 1 or 2, wherein pH 7-9 promoted Raney-nickelis used as a catalyst, in an amount of 0.05-0.5 part of mass.
 4. Theprocess according to claim 1, wherein the reduction is performed at atemperature between 25-100° C.
 5. The process according to claim 1,wherein the reduction is performed by using hydrogen under a pressure of1-20 bar.
 6. The process according to claim 4 wherein the temperature isbetween 50-100° C.
 7. The process according to claim 5 wherein thepressure is 5-10 bar.